Familial Amyloid Cardiomyopathy; Familial Amyloid Polyneuropathy; Leptomeningeal Amyloidosis; Familial Oculoleptomeningeal Amyloidosis

Transthyretin (TTR) amyloidosis is characterized by a slowly progressive neuropathy and other problems associated with amyloid deposition in the heart, kidney, eye, and central nervous system. The disorder has a particularly high prevalence in Japan and Portugal, where onset is earlier (between ages 20 and 40) than in other regions. Reduced and age-related penetrance is observed, as well as variable expressivity. A small number of genotype-phenotype correlations have been documented.

TTR amyloidosis is an autosomal dominant condition caused exclusively by mutations in the TTR gene. The most frequent mutation, p.Val30Met, has been reported in individuals from many different ethnic backgrounds and is particularly common among Japanese, Portugese, and Swedish cases. Point mutations in TTR gene account for over 99% of disease alleles.

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of TTR amyloidosis.
2. Prenatal testing (technically feasible but not routinely performed – contact MGL to discuss):
   1. Pregnancies at risk of TTR amyloidosis where one of the parents has a pathogenic mutation in TTR.
3. Presymptomatic testing:
   1. Adults at risk of TTR amyloidosis due to a family history of molecularly confirmed TTR amyloidosis. Predictive testing will only be performed following genetic counselling by a recognized genetic service.

Bidirectional Sanger sequencing of the entire coding region and flanking intronic sequences of the TTR gene.

NM_000371.3 The ‘A’ within the initiation codon, ATG, is designated as nucleotide number 1.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., large genomic deletions/duplications, promoter mutations, regulatory element mutations).

For carrier/predictive testing due to a family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.